ASH Review from Medscape

I plan to write about a few more interesting sessions from ASH that dealt with Follicular Lymphoma, but today I thought I'd let some experts do the talking.

Medscape asked two Hematology experts (Dr. Ann LaCasce and DR. Kerry Savage) to review the ASH meeting and talk about the things that they thought were significant. As the headline for the article indicates, sessions dealing with CAR-T were big news (we're going to keep seeing CAR-T news for a while, I think, as a treatment for Lymphoma and for a bunch of other cancers -- and it's only going to get more effective as time goes on and researchers learn more about how it works). But there were also a lot of "negative trials," where the outcome wasn't as good as researchers had hoped.

Of course, the big news for Follicular Lymphoma was the success of Obinutuzumab as an addition to chemotherapy (O-CHOP instead of R-CHOP, for example). Interestingly, Dr. Savage is not willing to call the study a game-changer, because there is still no data for Overall Survival, and Obinutuzumab might cost more and have more side effects that Rituxan. Time will tell how much of a change this study brings about for clinical oncologists (the folks we see at our regular appointments).

The link above will take you to a video of their conversation. They discuss lots of things from ASH, not just FL news. (And sometimes Medscape articles are hard to get to through a link, so if you can't access the article, I'm including a transcript below, which Medscape was kind enough to provide with the original article.)

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Ann S. LaCasce, MD, MSc: Welcome to Medscape Oncology Insights. I am Ann LaCasce, associate professor of medicine at Harvard Medical School and senior physician at Dana-Farber Cancer Institute. Joining me today is Kerry Savage, associate professor at the University of British Columbia and a medical oncologist and clinical scientist at the BC Cancer Agency. We are at the American Society of Hematology (ASH) 2016 Annual Meeting in San Diego, where there have been a number of important lymphoma studies that we would like to highlight for you.
Kerry, what do you think is the most interesting abstract being presented at the meeting this year?
Kerry Savage, MD: It's tough. There were a few interesting phase 3 studies that came out, but for me, and I think for a lot of lymphoma specialists, we were waiting for the CALGB study comparing dose-adjusted EPOCH-R with R-CHOP.^[1] This included newly diagnosed diffuse large B-cell lymphoma. Disappointingly, but probably not surprisingly, this was a negative study with equivalent event-free survival and more toxicity with the dose-adjusted EPOCH-R. We are eagerly awaiting the subgroup analyses to see if there are subsets that may benefit.
Dr LaCasce: Do you think the subset analyses will yield anything? For instance, in primary mediastinal lymphoma, where there seemed to be a signal that suggested that EPOCH is more effective.
Dr Savage: I'm hoping, but I'm not sure the numbers will be there since it's only about 6% of the whole population. But I certainly want to see those data. The one I am most interested in is the GCB cell-of-origin subtype from the previous phase 2 studies. It seems like that was the subtype that would benefit, given the proliferative drive as opposed to the antiapoptotic effect and NF-B pathways of activated B. I am hoping that we see some of that data, but it might come out at a future date.
Dr LaCasce: In terms of double-hit or double-protein expressors, maybe we will get some information on that.
Dr Savage: Again, I think the double-hit might be too infrequent, at 5%. For the dual expressor, I am not holding my breath for that because most are activated B, and that is not the group that I think will see the benefit. For me, that is the talk I want to hear the most, even though it is a negative study. It is a really important study.
Dr LaCasce: What about the GOYA study^[2] with obinutuzumab?
Dr Savage: The GOYA study was on newly diagnosed diffuse large B-cell lymphoma, but this time comparing R-CHOP with obinutuzumab (GA101). Again, it was a negative study. There seemed to be no benefit from the addition of obinutuzumab. There is, in the abstract, a suggestion that perhaps there might be a benefit in the GCB subtype, so we will be looking to see that. It's disappointing that we haven't seen the benefits of these additional agents in diffuse large B-cell lymphoma.
Dr LaCasce: In terms of the toxicity of that antibody, do you think the signal was impressive or not that important?
Dr Savage: I think it's important. We see a lot of infusion-related reactions with obinutuzumab as well as additional infection and neutropenia.
Dr LaCasce: In terms of obinutuzumab and follicular lymphoma, the plenary, we had a big study looking at obinutuzumab versus rituximab in upfront follicular lymphoma.^[3] Do you think this will change practice?
Dr Savage: It's an interesting study. As a reminder, it was a study comparing any chemotherapy backbone—it could have been CVP, CHOP, or bendamustine with rituximab—with the same chemotherapy backbone and obinutuzumab. That was actually a positive study, which is why it's in the plenary session for progression-free survival. If you look at the curves, the absolute benefit is still quite small. It is only about 4%-5%. And again, we have the additional toxicity that we already talked about, such as infusion-related neutropenia and infection. And, of course, there is cost on top of that. Given that this is a chronic disease, we still don't know about overall survival. I am not sure how that's going to follow in terms of being practice-changing.

Dr LaCasce: In terms of maintenance, do you think it impacts how you assess the results of the study?
Dr Savage: Potentially, although both arms got maintenance.
Dr LaCasce: There was a hint of more secondary malignancies. Do you think that's real? It was a large randomized study.
Dr Savage: It's interesting. I am wondering if that will come out when we hear the discussion. There are double the number of secondary malignancies, but they are still low overall (6% versus 3%-4%), and it is early to be seeing that. I think we need more details. I would like to know if those are all solid tumors or if there could be some transformation events. That is something we will have to watch for and probably see some more mature follow-up.
Dr LaCasce: Mechanistically, it does not make sense. Something that everyone is looking forward to is seeing some more data on CAR T cells. What do you think about the late-breaking abstract on diffuse large B-cell lymphoma^[4] and the other abstract looking at transformed follicular and mediastinal lymphoma?^[5]
Dr Savage: It's exciting. These are patients who do not have any other options, and we have seen excellent efficacy in T-cell acute lymphoblastic leukemia (TALL). Now we are seeing this therapy spill into the lymphoma world. I'm very interested in the late-breaking abstract looking at a fairly large dataset of relapsed/refractory diffuse large B-cell lymphoma with CAR T-cell therapy.^[4] The CR rate is almost 50%. The duration of follow-up is still short. I think they are only looking at 1 and 3 months. So, the big question is: How durable are these responses? Considering how heavily pretreated this population is, these are very encouraging results. Similar findings were in the transformed and primary mediastinal population as well. Again, a difficult-to-treat population.
Dr LaCasce: Maybe a hint that they may respond a little bit better. What about the toxicity?
Dr Savage: Always the flip side. The cytokine release syndrome is worrisome. This can only be given in specialized centers that are attached to ICUs. Also, the signal of neurotoxicity still raises concerns. Can we strike that balance of efficacy and toxicity? We will have to see more data on that.
Dr LaCasce: Yes, it will be interesting to see how that's scaled up and taken to a much broader group of patients. What about mantle cell lymphoma? The maintenance rituximab after autotransplant^[6]—those data were compelling. Do you think that will change practice?
Dr Savage: I think it could. Some people are probably already using rituximab in the maintenance setting. This was a well-designed phase 3 study showing a benefit in progression-free survival with the addition of maintenance rituximab.^[6] It was quite a significant difference in the progression-free survival—about 20%. Rituximab was given every 2 months for 3 years. It's a little bit different from other settings. Whether you need it for that long, I don't know, but it could potentially be practice-changing. It was a well-conducted study.
Dr LaCasce: It looked like the toxicity was not that different between the two arms. What about Hodgkin's lymphoma? We are going to see some data in the first relapse setting combining brentuximab and nivolumab.^[7] What do you think about those data?
Dr Savage: It's interesting. The data we have seen so far with the checkpoint inhibitors have all been in patients post-transplant, or there have not been a lot pre-transplant. The design of this trial was to function as a salvage regimen as a lead-in to transplants: brentuximab vedotin and nivolumab, a phase 1/2 study, and four cycles. The response rate is very high at 92%, with a CR rate of about 60%. It is higher than what you would expect with nivolumab and a little bit better than what you would expect with brentuximab. There is certainly some rationale to combining them, and there is synergy. Brentuximab is immunogenic. Of course, we need to see longer-term follow-up and the progression-free survival, but I think we are going to be seeing more studies like this in that setting in Hodgkin's lymphoma.
Dr LaCasce: As we are seeing more patients getting brentuximab earlier, and maybe with the results of the randomized study, how are we going to move this forward?
Dr Savage: It's difficult. Depending on how ECHELON-1, the phase 3 upfront study, reads out, the rules are all going to change. Is the efficacy going to be as good? We have some data to support that brentuximab in the re-treatment setting works. I think the limitation will be peripheral neuropathy and the toxicity associated with it. We will need more data to know whether the landscape is going to change if brentuximab becomes incorporated into frontline therapy.
Dr LaCasce: Do you think there will still be a role for autologous transplants if we have these combination studies that have high complete remission rates?
Dr Savage: I have to admit that I'm still on that. I would not want to deny a transplant. We have such good data that transplants are curable. The stakes are high in this young population. Would you be willing to do a trial that does not do transplant? You'd really have to think carefully about how to design that trial and the patient population.
Dr LaCasce: It seems like there aren't really any interventions that have changed overall survival, so maybe it would be open to study.
Last, in cutaneous T-cell lymphoma, there was a randomized study comparing brentuximab with investigator choice.^[8] How do you interpret that study?
Dr Savage: That was an interesting study. Patients had to have had one prior therapy, and then they were randomized to either brentuximab or investigator's choice of methotrexate or bexarotene. There was a striking difference in outcome. They had an interesting primary endpoint. It was ORR4, which means overall response rate sustained for 4 months. It was significantly better in the brentuximab arm, at about 56%. Looking at the conventional response rate, it was hitting around 60%. There was a striking difference in median progression-free survival of almost 1.5 years versus about 3-4 months. This is definitely practice-changing. This is a difficult-to-treat population. It is difficult to assess response, but they did their best to use this global score to assess response. The data are quite compelling that we are going to see brentuximab used in this setting.
Dr LaCasce: Thank you, Kerry, for joining me for a very interesting discussion, and thank you for joining us both for this edition of Medscape Oncology Insights. This is Ann LaCasce with Kerry Savage, reporting from ASH 2016.